A novel cationic arginine-modified Self-Nanoemulsifying drug delivery system (SNEDDS) for improved anticancer and antioxidant activities of Naringin

Abstract

Naringin (NRG) is a flavonoid derived from citrus fruits. Despite its pharmacological significance, NRG’s therapeutic effectiveness is constrained by its unusual physicochemical characteristics, such as its lower aqueous solubility. This study was intended to develop an alkylated arginine (AL-ARG) containing self-nanoemulsifying drug delivery system (SNEDDS) serving as a positively charged amphiphile for enhanced anticancer and antioxidant activities of NRG. The drug solubility along with emulsification investigations resulted in the development of a ternary phase diagram for selected suitable formulation components. Lipid (cinnamon oil), surfactant (labrasol), and co-surfactant (Transcutol) were selected as the main components of the formulation. FTIR, zetasizer, and atomic force microscope were employed to characterize optimized formulations, which were then tested for dilution and thermodynamic stability.

It was found that the average droplet size and zeta potential of NRG-SNEDDS were 118.47 ± 21.16 nm and −21 ± 2.10 mV, respectively, while those of AL-ARG-incorporated NRG-SNEDDS were 162.17 ± 19.11 nm and −17 ± 1.83 mV. The developed SNEDDS were extremely stable and did not change the chemical nature of the drug. The developed SNEDDS were tested for their antioxidant activity, and the findings showed that the antioxidant potential of NRG was greatly improved by its incorporation into the AL-ARG-modified SNEDDS. When AL-ARG was incorporated into NRG-SNEDDS, its anticancer potential was greatly increased against the human chronic myeloid leukemia cell. It can be concluded that novel cationic arginine-modified SNEDDS have the potential to substantially enhance the antioxidant and anticancer properties of NRG.

Introduction

Cancer is the main cause of death all over the world. Cancer is the primary or secondary reason for mortality in 113 nations in 2019, according to World Health Organization (WHO) data [1]. 10.0 million cancer-related deaths were recorded globally in 2020, and there were 19.3 million newly diagnosed instances of cancer [2]. High cancer mortality rates may be associated with insufficient information about the disease and its treatment. In addition to being difficult and time-consuming, developing a new drug is complicated by the adverse effects of current conventional cancer treatments like radiotherapy [3] and chemotherapy [4], which adds to the burden and complicates the process of treating cancer patients. Additionally, the majority of currently available anticancer medications are primarily constrained by their nonselectivity of cytotoxic activity and their limited therapeutic index [5]. In recent years, due to the emergence of drug resistance, there has been a rise in interest in cancer treatments based on plant-derived natural compounds [6]. Utilization of naturally occurring, biocompatible anticancer substances can therefore be considered a safe and promising option.

Flavonoids are compounds that can be found naturally in fruits and vegetables, and they have recently gained increased pharmacological significance. Naringin (NRG) is a citrus fruit-derived flavonoid. Due to its diverse pharmacological properties, it has been incorporated into a wide variety of European plant therapeutic formulations. Because of its promising anti-cancer, antioxidant, and anti-inflammatory properties, it has been considered as a representative flavonoid [7], [8]. NRG is a potential anticancer agent because it has been demonstrated to induce cytotoxicity by inducing apoptosis in P388 mouse leukemia cells [9]. NRG’s efficacy against liver cancer may also be influenced by its capacity to neutralize free radicals and serve as an antioxidant [10]. Flavonoids’ therapeutic effectiveness is always slowed by factors like their poor water solubility and aqueous dissolution rates, sensitivity to oxidation, and susceptibility towards degradation in acidic pH [11]. NRG’s lower water solubility has posed a significant challenge for formulation scientists because it is the rate-limiting stage in its body absorption, which results in its lower therapeutic efficacy [12]. Alternative NRG formulations, such as Nano-sized drug delivery systems (DDS), would therefore be necessary to prevent the drug from degrading in the gut, increase its bioavailability, and provide a sustained release of the drug to enhance its therapeutic efficacy [13]. Additionally, improving its water solubility and shielding it from oxidation would be possible ways to improve its therapeutic effectiveness.

Lipid-based DDS (LBDDS) has been widely employed to improve the absorption, solubility, and eventually the bioavailability of lipophilic drugs [14], [15]. Self-nano-emulsifying drug delivery systems (SNEDDs) are thought to be possible nanocarriers for protecting drugs from the harsh GI environment among LBDDS [16]. The formulation of SNEDD is a composition of surfactants, oils, and co-surfactant in addition to the medicinal substance, which can result in the formation of an oil–water nano-emulsion. When exposed to the GI medium, the nano-emulsion simultaneously forms and breaks down into nanodroplets (globule size: 100 nm), which have a large surface area and promote rapid drug uptake. Since SNEDDS nanodroplets have lipophilic properties, they can carry a large quantity of hydrophobic drugs while also preventing enzymatic hydrolysis [17], [18].

The incorporation of absorption enhancers can further increase the permeability of SNEDDS across cellular membranes. Cationic nanosystems have recently attracted more attention because of their inherent potential to interact with negatively charged surfaces or biomolecules [19]. For instance, several cationic surfactants were formed and used in the nanoemulsion system. Their loaded preconcentrate was subsequently spontaneously self-emulsified to generate cationic surfactant-anchored nanoglobules, which were discovered to improve the permeability of small drug molecules [20], [21]. Successful methods for delivery of anticancer drug to solid tumors include cationic nano systems, which have favorable electrostatic interactions with anionic substances such glycoproteins, proteoglycans, and anionic phospholipids present in the tumor microvasculature.

Quaternary ammonium-based traditional cationic surfactants (TCS) have shown that nanosystems are capable of transporting drugs into the body and generally exhibiting excellent anticancer activity [22], [23]. TCS, however, exhibit hemolytic activity, making them unsuitable for use in medical uses [24]. Therefore, amino acid-derived cationic amphiphiles may represent a viable replacement for the more commonly used synthesized TCS. Their biodegradability, minimal cytotoxic potential, and use of renewable materials in their production make them preferable to other cationic surfactants [25]. Among the previously reported cationic amino acid-based surfactants, lysine and arginine have yielded the most encouraging results [26], [27]. Because of these characteristics, cationic surfactants derived from amino acids are a good choice for distinctive biomedical applications.

The present study was aimed to develop NRG-loaded SNEDDS with improved permeation across biological membranes by incorporating alkylated arginine (AL-ARG) as a permeation enhancer. This is, to the best of our knowledge, the first investigation to examine the effect of SNEDDS-containing AL-ARG based permeation enhancer towards improved anticancer and antioxidant activities of NRG.

Read more here

Materials

In this study, organic solvents of analytical quality were utilized. Tween 20, Tween 80, soya bean oil, coconut oil, cinnamon oil, cedarwood oil, cardamom oil, nutmeg oil, polyethylene glycol 400 (PEG 400), PEG 200, transcutol, labrasol, and capryol were acquired from Merck Darmstadt (Germany). L-Arginine was acquired from Sigma-Aldrich.

Tasmina Kanwal, Khadija Rehman, Huzaifa Muhammad Hamid, Ali Asgher Shuja, Salim Saifullah, Tauseef Ahmed, Muhammad Hasnain, Shabana Usman Simjee, Muhammad Raza Shah, A novel cationic arginine-modified Self-Nanoemulsifying drug delivery system (SNEDDS) for improved anticancer and antioxidant activities of Naringin,
Journal of Molecular Liquids, Volume 391, Part A, 2023, 123235, ISSN 0167-7322, https://doi.org/10.1016/j.molliq.2023.123235.

See the webinar:

“Rational Selection of Cyclodextrins for the Solubilization of Poorly Soluble Oral Drugs”, 8. November 2023:

Get more information & register here for free: